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T Cell Activation and Clonal Selection

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Generation of Human Chimeric Antigen Receptor Regulatory T Cells
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An obligate cell-intrinsic function for CD28 in Tregs.

Ruan Zhang1, Alexandria Huynh, Gregory Whitcher

  • 1Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

The Journal of Clinical Investigation
|January 3, 2013
PubMed
Summary

Regulatory T cells (Tregs) require CD28 for optimal function. Treg-specific CD28 knockout mice developed severe autoimmunity, demonstrating CD28

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Regulatory T cells (Tregs) expressing FOXP3 are crucial for maintaining immune homeostasis.
  • The costimulatory molecule CD28 is vital for naive T cell activation but its role in Treg function is complex due to its requirement for thymic Treg development and potential off-target effects of blockade.

Purpose of the Study:

  • To investigate the specific postmaturational role of CD28 in FOXP3+ Tregs.
  • To elucidate the mechanisms by which CD28 influences Treg function and immune regulation.

Main Methods:

  • Generation of Treg-specific Cd28 conditional knockout mice.
  • Assessment of immune homeostasis, autoimmune development, and experimental allergic encephalomyelitis resolution in knockout mice.
  • Analysis of Treg function, including expression of immune markers and competitive repopulation assays.

Main Results:

  • Treg-specific Cd28 knockout mice exhibited normal FOXP3+ cell numbers but developed severe, multi-organ autoimmunity (skin, lungs) and failed to resolve experimental allergic encephalomyelitis.
  • Impaired Treg function was associated with reduced expression of CTLA-4, PD-1, and CCR6.
  • Cd28-deficient Tregs showed a significant proliferative/survival disadvantage in competitive environments, and disease was prevented by complementation with normal Tregs, ruling out Treg-to-pathogenic cell conversion.

Conclusions:

  • CD28 plays a critical postmaturational role in FOXP3+ Tregs, essential for maintaining immune homeostasis and preventing autoimmunity.
  • CD28 deficiency in Tregs leads to functional impairment, characterized by reduced expression of key immune markers and a competitive disadvantage, contributing to autoimmune disease development.
  • These findings offer novel insights into the mechanisms by which CD28 signaling regulates Treg function independently of thymic development or effects on other immune cells.